Clinical characteristics and outcomes in patients with acute myeloid leukemia with concurrent FLT3-ITD and IDH mutations

Mahran Shoukier, Tapan Kadia, Marina Konopleva, Ahmad S. Alotaibi, Mansour Alfayez, Sanam Loghavi, Keyur P. Patel, Rashmi Kanagal-Shamanna, Jorge Cortes, Bachar Samra, Elias Jabbour, Guillermo Garcia-Manero, Koichi Takahashi, Sherry Pierce, Nicholas J. Short, Musa Yilmaz, Koji Sasaki, Lucia Masarova, Naveen Pemmaraju, Gautam BorthakurHagop M. Kantarjian, Farhad Ravandi, Courtney D. DiNardo, Naval Daver

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co-occur with FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML). Methods: The authors reviewed cases of patients with FLT3-internal tandem duplication (FLT3-ITD)–mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018. Results: A total of 91 patients with FLT3-ITD and IDH1 or IDH2 “double-mutated” AML were identified; 36 patients had concurrent FLT3-ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3-ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single-agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting. Conclusions: The combination of FLT3I-based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3-ITD/IDH co-mutated disease. Fewer patients with double-mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach. Lay Summary: The prognostic influence of FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) and isocitrate dehydrogenase (IDH) co-mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non–FLT3/IDH inhibitor–based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available. The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low-intensity therapy appears to be an effective approach in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.

Original languageEnglish (US)
JournalCancer
DOIs
StateAccepted/In press - 2020

Keywords

  • acute myeloid leukemia
  • FLT3 and/or IDH inhibitors
  • FMS-like tyrosine kinase 3 (FLT3) with the internal tandem duplication (ITD) mutation
  • isocitrate dehydrogenase (IDH) mutations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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